Title |
Exposure–safety–efficacy analysis of single-agent ixazomib, an oral proteasome inhibitor, in relapsed/refractory multiple myeloma: dose selection for a phase 3 maintenance study
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Published in |
Investigational New Drugs, April 2016
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DOI | 10.1007/s10637-016-0346-7 |
Pubmed ID | |
Authors |
Neeraj Gupta, Richard Labotka, Guohui Liu, Ai-Min Hui, Karthik Venkatakrishnan |
Abstract |
Background Ixazomib is the first oral, small molecule proteasome inhibitor to reach phase 3 trials. The current analysis characterized the exposure-safety and exposure-efficacy relationships of ixazomib in patients with relapsed/refractory multiple myeloma (MM) with a purpose of recommending an approach to ixazomib dosing for maintenance therapy. Methods Logistic regression was used to investigate relationships between ixazomib plasma exposure (area under the curve/day; derived from individual apparent clearance values from a published population pharmacokinetic analysis) and safety/efficacy outcomes (hematologic [grade ≥ 3 vs ≤ 2] or non-hematologic [grade ≥ 2 vs ≤ 1] adverse events [AEs], and clinical benefit [≥stable disease vs progressive disease]) using phase 1 data in relapsed/refractory MM (NCT00963820; N = 44). Results Significant relationships to ixazomib exposure were observed for five AEs (neutropenia, thrombocytopenia, rash, fatigue, and diarrhea) and clinical benefit (p < 0.05). Dose-response relationships indicated a favorable benefit/risk ratio at 3 mg and 4 mg weekly, which are below the maximum tolerated dose of 5.5 mg. At 3 mg, the model predicted that: 37 % of patients will achieve clinical benefit; incidence of grade ≥ 3 neutropenia and thrombocytopenia will be 10 % and 23 %, respectively; and incidence of grade ≥ 2 rash, fatigue, and diarrhea will be 8 %, 19 %, and 19 %, respectively. Conclusions Based on the findings, patients in the phase 3 maintenance trial will initiate ixazomib at a once-weekly dose of 3 mg, increasing to 4 mg if acceptable tolerability after 4 cycles, to provide maximum clinical benefit balanced with adequate tolerability. |
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Unknown | 35 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
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Other | 5 | 14% |
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Student > Ph. D. Student | 3 | 9% |
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Unknown | 11 | 31% |
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Other | 2 | 6% |
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